European journal of haematology · 2020
RLTPR Q575E: A novel recurrent gain-of-function mutation in patients with adult T-cell leukemia/lymphoma.
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Uchida Yuichiro, Yoshimitsu Makoto, Hachiman Miho, Kusano Shuichi, Arima Naosuke, Shima Kodai, Hayashida Maiko, Kamada Yuhei, Nakamura Daisuke, Arai Akihiko, Tanaka Yuetsu, Hara Hiromitsu, Ishitsuka Kenji
Аннотация
OBJECTIVES: Adult T-cell leukemia/lymphoma (ATL) is an intractable T-cell malignancy caused by long-term infection with human T-cell leukemia virus type-1 (HTLV-1). While ATL pathogenesis has been associated with HTLV-1-derived oncogenic proteins, including Tax and HBZ, the contribution of genomic aberrations remains poorly defined.
METHODS: To elucidate the genomic basis of ATL, whole exome sequencing was performed on cells from 47 patients with aggressive ATL.
RESULTS: We discovered the novel mutation RLTPR Q575E in four patients (8.5%) with a median variant allele frequency of 0.52 (range 0.11-0.68). Despite being reported in cutaneous T-cell lymphoma, three ATL patients carrying RLTPR Q575E lacked skin involvement. Patients carrying RLTPR Q575E also harbored CARD11 (75%), PLCG1 (25%), PRKCB (25%), or IKBKB (25%) mutations related to TCR/NF-κB signaling. Jurkat cells transfected with RLTPR Q575E cDNA displayed increased NF-κB activity and significantly increased IL-2 mRNA levels under stimulation. RLTPR Q575E increased the interaction between RLTPR and CARD11, while RLTPR directly interacted with Tax.
CONCLUSIONS: We identified, and functionally validated, a novel gain-of-function mutation in patients with aggressive ATL. During TCR activation by Tax or gain-of-function mutations, RLTPR Q575E selectively upregulates NF-κB signaling and may exert oncogenic effects on ATL pathogenesis.
METHODS: To elucidate the genomic basis of ATL, whole exome sequencing was performed on cells from 47 patients with aggressive ATL.
RESULTS: We discovered the novel mutation RLTPR Q575E in four patients (8.5%) with a median variant allele frequency of 0.52 (range 0.11-0.68). Despite being reported in cutaneous T-cell lymphoma, three ATL patients carrying RLTPR Q575E lacked skin involvement. Patients carrying RLTPR Q575E also harbored CARD11 (75%), PLCG1 (25%), PRKCB (25%), or IKBKB (25%) mutations related to TCR/NF-κB signaling. Jurkat cells transfected with RLTPR Q575E cDNA displayed increased NF-κB activity and significantly increased IL-2 mRNA levels under stimulation. RLTPR Q575E increased the interaction between RLTPR and CARD11, while RLTPR directly interacted with Tax.
CONCLUSIONS: We identified, and functionally validated, a novel gain-of-function mutation in patients with aggressive ATL. During TCR activation by Tax or gain-of-function mutations, RLTPR Q575E selectively upregulates NF-κB signaling and may exert oncogenic effects on ATL pathogenesis.
Предметные рубрики MeSH
AdultAgedAllelesAmino Acid SubstitutionFemaleGain of Function MutationGene ExpressionGenetic Association StudiesGenetic Predisposition to DiseaseGenetic VectorsGenotypeHuman T-lymphotropic virus 1HumansLeukemia-Lymphoma, Adult T-CellMaleMicrofilament ProteinsMiddle AgedMutationNF-kappa BRetroviridaeSignal TransductionExome Sequencing